Linkage and purely family-based studies have successfully identified many cancer susceptibility genes. Mutations in these high-penetrance genes account for most of the several percent of cancers (at all or most sites) that occur in autosomal dominant Mendelian patterns. But it is generally agreed that case-control association studies, or other large epidemiologic study designs, such as cohort studies, will be required to identify most of the remaining low-penetrance susceptibility loci and that these will probably not yield to study designs that are entirely family-based. Such studies involve comparing the prevalence of particular alleles at candidate genetic loci between subjects with a disease, such as breast cancer, and appropriately selected control subjects without the disease. The tested locus can be either the biologically relevant one, or a marker locus that is in linkage disequilibrium with the biologically relevant allele (with an attendant increase in the required sample size).The molecular pathway that we have concentrated on most with regard to possible cancer susceptibility alleles is DNA damage repair. We have developed Taqman assays for over 40 SNPs (largely derived from dbSNP or the medical literature), most of which are in DNA repair genes.In addition to evaluating SNPs as susceptibility alleles for several cancer sites, we are studying the potential biological relevance of the many SNPs in DNA repair genes using a panel of lymphoblastoid cell lines derived from subjects in the x-ray technologist cohort. These studies were planned and are being conducted in collaboration with Alice Sigurdson (DCEG) and Irene Jones of Lawrence Livermore National Laboratory. Dr Jones has performed a functional measure of DNA repair capacity, the single-cell gel electrophoresis or Comet assay, which measures a cells ability to repair breaks. We will perform genotyping assays in Building 41 for all known SNPs in base excision repair (BER) genes and will have the capacity to analyze other genes, particularly if other functional assays, tailored to measure other types of DNA damage, are performed on this panel of cell lines. In addition, we have begun mRNA expression studies using the Affymetrix U133 chip set on a blinded subset of samples representing those with the best and poorest functional base excision repair as measured by the Comet assay. In collaboration with Dr Sigurdson and Michael Hauptmann (Biostatistics Branch, DCEG) we will correlate the genotyping and mRNA expression results to see which are associated with functional repair capacity.We are collaborating on two large NCI epidemiologic studies of breast cancer, including a case-control and a cohort study. In addition, we are evaluating DNA repair SNPs in a case-control study of thyroid nodules and thyroid cancer among subjects exposed to radiation at a nuclear test site in Kazakhstan.